Significant Items in House & Senate Appropriations Committee Reports

FY 2007 Budget

Parkinson's disease - The Committee encourages NIEHS to continue funding research into environmental influences of Parkinson's disease. The causes of Parkinson's and other neurodegenerative disorders are increasingly shown to be a result of the inter-relation of environment and genes. Possible environmental triggers of Parkinson's are pesticides and/or heavy metals. If these environmental toxins can be identified and the mechanisms elucidated, appropriate prevention or treatment may prevent many cases of Parkinson's, especially concerning increasingly younger persons at risk. (p. 85)

Action taken or to be taken

Parkinson's and other neurodegenerative diseases continue to be priority areas for NIEHS and a number of mechanisms are used to encourage research in this area. NIEHS currently supports a significant number of investigator-initiated studies in Parkinson's disease. Additional applications are solicited actively through a Program Announcement with a $2 million dollar set-aside, PAS 03-160: "Gene-Environment Interactions in Neurodegenerative Disease." NIEHS supports a national network, the Collaborative Centers for Parkinson's Disease Environmental Research (CCPDER). These Centers focus on gene-environment interactions in disease etiology; pesticides and metals are among the toxicants under study. In addition to providing support for self-contained research conducted at each CCPDER, NIEHS has made additional funds available to CCPDER investigators to support several network projects. These collaborative projects are aimed at (1) developing improved animal models; (2) creating a screening battery for identifying potential environmental toxicants that may contribute to Parkinson's; and (3) developing a risk factor instrument that will facilitate data sharing and pooling among epidemiologists studying Parkinson's. Finally, NIEHS continues to supports meetings and conferences that focus on environmental aspects of Parkinson's.

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Mercury - In order to properly research gaps in the area of mercury exposure and brain chemistry, and given recent hearings on mercury exposure and relationships between autism and Alzheimer's disease and mercury exposure, NIEHS is encouraged to pursue studies of how inorganic mercury and organic mercury compounds (including ethyl, methyl, and other forms of mercury from all sources) are processed in the bodies of children and adults. NIEHS is also encouraged to support studies of the toxic effects of inorganic mercury and organic mercury compounds on the nervous systems of young children, adults, and the elderly and methods of properly removing mercury and mercury-containing compounds from the brains of affected humans. (p. 85)

Action taken or to be taken

NIEHS recognizes that environmental mercury exposure is an important public health concern and provides ongoing funding for a number of studies in this area. Together with the US EPA, NIEHS funds a large epidemiologic investigation to determine the relationship between a range of environmental exposures, including mercury and other metals, and the risk of autism spectrum disorders (ASD). NIEHS has provided additional funding to investigators to support a replication study of the recent published finding by another group of investigators of strain-dependent differences in sensitivity to the mercury-based preservative thimerosal.

Within the autism arena, NIEHS works collaboratively with other NIH institutes and federal agencies to support a number of autism research initiatives and activities. NIEHS is a cosponsor of a broadly-based program announcement that encourages investigators to submit new applications addressing autism etiology, treatment and other priority items relevant to autism. NIEHS plans to contribute to the funding of the new NIH Autism Centers of Excellence Program that is being developed and will encourage applicants to include studies that address environmental influences in autism. Finally, NIEHS is working collaboratively with the National Institute of Mental Health (NIMH) to explore the feasibility of conducting a small clinical trial of chelation therapy with succimer in individuals with autism. NIEHS has significant expertise in this area and supported the development and application of succimer as a treatment for heavy metal poisoning.

NIEHS continues to support very basic research to appreciate at the molecular level, the toxicity of mercury to the brain, especially the developing brain. These range from the methylmercury effect on mitochondrial oxidative function, on the extreme sensitivity of the GABAA transmitter receptor, on the development of microphthalmia in children, on the relative contributions of different forms of mercury on neurobehavioral defects as well as a potential biomarker for a possible predisposition to altered mercury susceptibility in humans. A project examining the mechanism(s) by which methylmercury is transported into the cell has identified a novel antidote/chelator for removal of methylmercury from the body using N-acetylcysteine.

NIEHS supports studies examining the effects of dietary ingestion of methylmercury on the developing brain Two are studying whether there are any lasting effects of mercury exposure in what are now adolescents and they will be able to correlate their findings to school performance. Two others center on whether nutrients from a fish diet can mitigate the effects of methylmercury exposure. This is especially relevant since a small pilot study has shown that the offspring of mothers who eat fish have better cognition at age two. But the two year-old offspring of mothers who have high exposure to mercury have poorer cognition.

NIEHS plans to continue to encourage investigator-initiated research in the field of mercury research including its effect on the immune system as well as the brain.

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Toxic exposure and brain development - Notwithstanding the Institute of Medicine May 2004 report on autism, the Committee believes it is important to develop a more complete understanding of the impact that toxic exposures may have on brain development. There is a convergence of findings from tissue culture studies, animal models, and clinical studies of immune dysfunction in children with autism and other neurodevelopmental disorders (NDDs) that suggests a biological link between genetic sensitivity and damage to developing brains from certain toxins. It is important that NIH continue this research to better understand the impact that exposures to mercury (including thimerosal) and other toxins have on brain development. A more complete understanding of the impact of these exposures through research, including animal models, will help to develop more effective interventions. (p. 85)

Action taken or to be taken

NIEHS recognizes the importance of understanding how a broad range of environmental exposures affect aspects of early development. Individual differences in susceptibility to exposure are a central theme in many NIEHS-supported research efforts. NIEHS, together with the Environmental Protections Agency (EPA), supports a national network of Children's Centers for Environmental Health and Disease Prevention. Several of these Centers focus on environmental contributors to neurodevelopmental disorders, including autism. NIEHS and EPA recently announced a new round of competition for these Centers; existing Centers and new teams of investigators are encouraged to apply; applicants are required to focus on neurodevelopmental and/or endocrine disorders. NIEHS and EPA expect to fund four Centers for a period of five years, contingent on a sufficient number of meritorious applications.

In addition to this Centers program, NIEHS supports many investigator-initiated grants in the area of neurodevelopment. These studies include population-based epidemiologic investigations in infants and children to animal and cellular models of toxicant action in developing brain.

NIEHS continues to provide support for a study aimed at determining the reliability of a recent finding demonstrating strain-dependent sensitivity to thimerosal administration in mice. This study will be completed within the next six months and submitted for publication in a peer-reviewed journal within a year. NIEHS also plans to provide expert advice for a study that will examine the brains of non-human primates exposed to thimerosal or methyl mercury early in development to determine any effects on cell type and number.

NIEHS is aware of the emerging findings of immune dysfunction in ASD. To encourage neurotoxicologists to study the interaction of environmental agents with the immune systems during early brain development, NIEHS sponsored a scientific session at the International Neurotoxicology Society meeting on September 12, 2005. This session was entitled: "Environmental Perturbations of the Immune System: Implications for Autism and Other Neurodevelopmental Disorders." The scientific session was followed by a small workshop of scientific experts in this area to identify research needs and opportunities. The results of this workshop will be used in planning future NIEHS activities.

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Toxicology validation reviews - In order for the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) to carry out its responsibilities under the ICCVAM Authorization Act of 2000, the Committee encourages NIEHS to strengthen the resources for methods validation reviews in FY 2006. The Committee is encouraged by the National Toxicology Program's Road Map and Vision for NTP's toxicology program in the twenty-first century and encourages NIEHS to move rapidly to implement the programs, especially those directly aimed at strengthening the scientific basis for many alternative methods (such as Quantitive Structure-Activity Relationships), mechanistic screens, high throughput assays, and toxicogenomics). (p. 85/86)

Action taken or to be taken

The development, validation, acceptance and harmonization of new, alternative, and revised toxicological test methods is coordinated within the federal government by ICCVAM, a permanent interagency committee of NIEHS under the National Toxicology Program Interagency Center for Evaluation of Alternative Toxicological Methods (NICEATM). NICEATM administers ICCVAM and provides scientific support for ICCVAM and ICCVAM-related activities including coordination of independent validation studies to evaluate the usefulness and limitations of proposed test methods. NICEATM has several goals for FY2006, all of which are supported by NIEHS: (1) Standardize and plan validation studies on a non-animal/non-radioisotopic estrogen receptor transcriptional activation test method to determine if this test method can replace current methods that require surgically manipulated animals; (2) Finalize and forward ICCVAM test method recommendations for four non-animal methods for identifying severe ocular irritants and corrosives; (3) Complete independent peer review evaluation of two in vitro cytotoxicity methods proposed for reducing the number of animals required for acute systemic toxicity studies and convene an expert workshop to identify the highest priority R&D and validation studies necessary to further reduce the number of animals required for acute toxicity; (4) Convene an expert workshop to identify high priority R&D and validation studies needed to further reduce animal use needed to determine the potency of botulinum toxin preparations; and (5) Identify priority validation needs for in vitro ocular irritancy testing and initiate planning of needed studies.

NIEHS appointed a new Deputy Director for NICEATM in June 2005. This additional person will allow for expansion of NICEATM activities and facilitate integration of NICEATM in the NTP Roadmap initiative on high throughput screening. NTP is working to identify or develop rapid, mechanism-based assays that can be used to screen large numbers of environmental substances for their potential biological activity. NTP plans to explore the use of this technology to predict how substances might react in biological systems and prioritize them for more extensive toxicological evaluation using fewer laboratory animals.

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Risk analysis - The Committee encourages NIEHS to establish a competitive, peer-reviewed extramural program of centers for risk sciences to conduct research in risk sciences, including assessment, management analysis, and communication of risks from exposure to environmental chemicals. NIEHS is encouraged to work with these centers to develop scientifically-based methodologies used to determine, quantify, and communicate risk to the public's health. (p. 86)

Action taken or to be taken

NIEHS, through the Superfund Basic Research Program (SBRP), supports a multidisciplinary research focus in the assessment of risk. This program was established under the Superfund Amendments and Reauthorization Act (SARA) of 1986 with specific mandates to develop a research program that, in part, advances techniques for the detection, assessment, and evaluation of the effects on human health of hazardous substances and develops methods to assess the risks to human health presented by hazardous substances. Through this research program, we encourage the development of new risk assessment models that describe risk from the source of contamination, through the movement of contaminants within environmental media, to its uptake by biological receptors (i.e., human or wildlife) and the effect within biological receptors on complex cellular and molecular pathways to the incipience of dysfunction or disease. SBRP also supports community outreach and research translation activities that include the development of risk communication strategies. In parallel efforts, NIEHS invests in basic research in exposure assessment and statistical methods that advances the underlying data necessary to develop and conduct scientifically sound risk assessments. Through initiatives such as the Community-Based Participatory Research Program, NIEHS conducts evaluation of risk communication strategies.

NIEHS supports these research efforts through a competitive peer-review process. NIEHS will continue to encourage anticipatory research and identify "emerging" issues, especially in pivotal sources of uncertainty that might affect the risk sciences.

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Asthma - Given the link between environmental factors and the onset of asthma, COPD, and pulmonary fibrosis, the Committee encourages NIEHS to further develop research initiatives, such as a large multi-center, long-term longitudinal, and maternal/birth cohort to understand the environmental and genetic risk factors for predisposing some individuals to and in controlling the severity of these lung diseases. (p. 86)

Action taken or to be taken

NIEHS agrees with the Committee that multidisciplinary research on the environmental and genetic factors that contribute to the development of asthma, COPD, and pulmonary fibrosis is an important priority and supports numerous multi-disciplinary, longitudinal research programs that include human populations and animal models. NIEHS supports the Children's Environmental Health and Disease Prevention Research Centers and investigator-initiated research grants that focus on the role of ambient air and environmental home contaminants on the development and severity of childhood asthma. In a longitudinal study of school children in twelve communities with varying levels of air pollution, the addition of genetic markers that may modulate the biological response to toxicants are examined. Deficits in lung growth and function have been associated with increased levels of air pollutants. Interactions between genes involved with metabolism and detoxification of these toxicants and oxidant stress are being examined. In epidemiologic and intervention research supported by NIEHS, exposures such as indoor allergens, and chemicals such as insecticides, pesticides, and phthalates are being examined as children grow and develop. Diesel exhaust particles, a constituent of truck exhaust, have been implicated in the development and exacerbation of lung diseases. Using a birth cohort design, NIEHS-funded researchers are examining the health risk to children residing near interstate highways who are exposed to high levels of diesel exhaust particles and finding allergic and respiratory responses in those highly exposed.

Animal models provide the opportunity to examine the cellular and molecular mechanisms through which environmental exposures induce lung disease. The neonatal response to oxidant air pollutants and allergens and the relationship of these exposures to development of childhood and adult asthma is being studied in a rhesus monkey model. Research will identify developmental "windows of susceptibility" in the first year of life and structural and functional changes in the neonatal lung that predispose individuals to pulmonary disease. Using clinical research tools, the genetics of complex lung disease are investigated through studies that model biologically unique gene-environment disease phenotypes. NIEHS research is exploring the role of the Toll-like Receptor 4 in airway responsiveness to endotoxin and the role of S-nitrosylation in the inflammatory component of lung disease. NIEHS has also initiated a program to investigate the effect of fetal exposure to environmental pollutants on the development of adult disease, including lung disease. Environmental pollutants employed in NIEHS animal studies include diesel exhaust particles, ozone, heavy metals, manufacturing chemicals such as toluene diisocyanante and dioxin, and environmental tobacco smoke. State-of-the-art technologies are encouraged, including genomics, to assess exposure-initiated changes in gene expression, proteomics to identify changes in the proteins that affect the response to exposure, and computer models to link in vitro and in vivo studies. It is through longitudinal human populations studies, clinical based inquires and laboratory based experimental research that advances in our understanding of the mechanisms of environmental exposures can be applied to the prevention and treatment of lung disease in children and adults.

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Asthma - Given the link between environmental factors and the onset of asthma, COPD, and pulmonary fibrosis, the Committee encourages NIEHS to further develop research initiatives, such as a large multi-center, long-term longitudinal, and maternal/birth cohort to understand the environmental and genetic risk factors for predisposing some individuals to and in controlling the severity of these lung diseases. (p. 128)

Action taken or to be taken

Please refer to the item regarding Asthma on pages NIEHS-33 and NIEHS-34 of this document for response to this Significant Item.

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Basic Behavioral and Social Sciences Research - The Committee encourages NIEHS to participate in trans-institute initiatives organized by OBSSR or another institute to strengthen basic behavioral or social science research, and to enhance opportunities for behavioral and social science research training. (p.128)

Action taken or to be taken

Over the past ten years, NIEHS and OBSSR have been strong partners in a number of joint initiatives. We have participated in a number of program announcements and Requests for Applications (RFAs) which have brought behavioral and social science research into the spectrum of disciplines in the environmental health sciences. Many of the NIEHS programs in environmental justice, community-based participatory research, and health disparities have been strengthened by working with OBSSR on these important issues. During 2005, NIEHS has been a member of the trans-NIH committee on behavioral and social sciences and will continue to devote staff time and resources to maintain our involvement with this group. During the last year, NIEHS participated with OBSSR and other ICs on a program announcement on health literacy, an RFA on obesity and the built environment, and a three-year program announcement to stimulate continued growth and application of community-based participatory research methods to study human health and disease. In each activity NIEHS is particularly interested in the application of intervention and behavioral methods to environmental health questions.

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Breast Cancer - The Committee believes that it is essential to support research on environmental factors that may be related to the etiology of breast cancer. The Committee recognizes the important first step the Institute has taken with its recently awarded grants to four research centers to begin to study the prenatal-to-adult environmental exposures that may predispose a woman to breast cancer. However, the recent awards are only a small down payment in terms of dollars, process, and focus on the comprehensive and collaborative research that is needed. The need for more funding and a comprehensive research strategy, as outlined by the Breast Cancer and Environmental Research Act, is clear. The Committee understands that the Institute will establish an advisory board to make recommendations to the Director with regard to the development of the research centers. The Committee is pleased that the board will include representatives from the breast cancer community who have had the disease. The Committee asks that the director provide an update in the FY 2007 appropriations justification on the progress of the centers. (p.128)

Action taken or to be taken

NIEHS and NCI are partnering to support a network of research centers in which multidisciplinary teams of scientists, clinicians, and breast cancer advocates work collaboratively on understanding the impact of early life exposures on breast cancer risk. An epidemiological study is underway to determine how environmental factors that are local to where young women live and learn may change the timing of puberty. Twelve hundred girls (ages 8 - 14) of diverse background are being evaluated to determine whether exposures and nutrition contribute to early onset of puberty, an established risk factor for breast cancer. Candidate exposures are also studied in depth using laboratory animals to better understand their mechanisms of action, genomic features, and tumor-promoting potential.

Results of preliminary studies are encouraging and are providing new insights into the interactions of genes and the environment. In a pilot study to determine which genes might interact with environmental conditions to predispose girls to earlier puberty, naturally-occurring variations in six estrogen-synthesis and -metabolizing genes were compared. An association was found between obesity and earlier breast development, but only among girls with a slow "estrogen synthesis allele profile," especially those girls with variations in the gene (Cyp19) that plays a role in testosterone-to-estrogen conversion.

In concert with the puberty study, Breast Cancer and Environmental Research Centers (BCERC) laboratory researchers are investigating the impact of diet and common exposures on the architecture and development of mammary glands in animal models. An important study - recently published by the Center at Michigan State University - characterizes the levels of cell receptor sub-types that modulate the effects of progesterone, a hormone that, together with estrogen, guides central processes in female development. The report is the first to demonstrate that the distribution of progesterone receptors changes during puberty and pregnancy and correlate with the appearance of specific structures within the mammary gland.

Another study revealed intriguing effects of phthalates and other endocrine disruptors, chemicals that leach out of plastic, on gene activity in rat mammary glands. The investigators saw changes in activity of a number of known and, as yet, unknown genes following treatment of nursing dams with bis-phenol A (BPA) or n-butyl benzyl phthalate (BBP). Surprisingly, a single gene appears to be continually down-modulated in the offspring under both these treatment conditions. Ongoing studies are being performed to confirm these observations and to determine the significance of the findings for the architecture of the mammary gland, onset and progression through puberty, and ultimately, the influence on breast tumor development.

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Built Environment - The Committee is pleased with the research that NIEHS is supporting on environmental factors, including built environment, and their relationship to the rising prevalence of obesity among youth and adults. The Committee urges NIEHS to continue work in this area, including transportation choices and their impact on public health outcomes. (p. 129)

Action taken or to be taken

On August 20, 2004, NIEHS, the National Cancer Institute (NCI), The National Institute of Child Health and Human Development (NICHD), the NIH Office of Behavioral and Social Sciences Research (OBSSR), and two Centers within the Centers for Disease Control (CDC) released RFA-ES-003, "Obesity and the Built Environment," to begin building a program of R01 and R21 research projects in two specific areas related to the built environment and obesity: understanding the role of the built environment in causing/exacerbating obesity and related co-morbidities; and developing, implementing, and evaluating prevention/intervention strategies that influence parameters of the built environment in order to reduce the prevalence of overweight, obesity and co-morbidities.

NIEHS committed $3 million to fund five R01 and three R21 grant proposals. In addition, NIEHS will administer three CDC-funded R21 projects. The purpose of the R01 studies, with up to five years of funding, is to provide solutions for alleviating the burden of obesity and being overweight in the U.S. by providing insights into treatment mechanisms or developing models for prevention. The purpose of the two-year R21 studies is to develop and validate built environment measures and methods of data collection. Applications selected for funding included longitudinal, cross-sectional and intervention studies in rural, urban and suburban areas and were chosen to create a diverse, balanced portfolio that will enable NIEHS to contribute significantly to the scientific understanding of environment-obesity interactions. Program funding began in September 2005. An Annual Meeting for the project investigators and NIH and CDC program staff is planned for Winter/Spring 2006. By funding this set of awards, NIEHS created a fully integrated research program to better understand how the environment has contributed to obesity and how environmental interventions can prevent or treat this condition.

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Interagency Coordinating Committee for the Validation of Alternative Methods [ICCVAM] - In order for the Interagency Coordinating Committee for the Validation of Alternative Methods [ICCVAM] to carry out its responsibilities under the ICCVAM Authorization Act of 2000, the Committee encourages the NIEHS to strengthen the resources for the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods [NICEATM] for ICCVAM for methods validation reviews in FY 2006. The Committee is encouraged by the National Toxicology Program's [NTP] Road Map and Vision for NTP's toxicology program in the 21st century and encourages NIEHS to move rapidly to implement the programs, especially those directly aimed at strengthening the scientific basis for many alternative methods (such as Quantitative Structure-Activity Relationships), mechanistic screens, high throughput assays, and toxicogenomics. (p. 129)

Action taken or to be taken

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Parkinson's Disease - The Committee encourages NIEHS to continue funding research into environmental influences of Parkinson's disease. The causes of Parkinson's and other neurodegenerative disorders are increasingly shown to be a result of the inter-relation of environment and genes. Possible environmental triggers of Parkinson's are pesticides and/or heavy metals. If these environmental toxins can be identified and the mechanisms elucidated, appropriate prevention or treatment may prevent many cases of Parkinson's, especially concerning increasingly younger persons at risk. (p. 129)

Action taken or to be taken

Please refer to the item regarding Parkinson's disease on page NIEHS-29 of this document for response to this Significant Item.

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Pacific Center for Environmental Health - The Committee commends the NIEHS for its prompt attention to the concerns of the citizens of Hawaii related to volcanic emissions, food and waterborne illnesses, fish contamination by pesticides and heavy metals, and pesticide residue in food and water. The Committee urges NIEHS to pursue an Environmental Health Sciences Center in Hawaii to research and address these environmental concerns and to seek workable solutions to improve the health of Pacific Islanders. (p. 129)

Action taken or to be taken

In 2005, NIEHS re-announced the NIEHS Core Centers grant program with changes which provide for a renewed focus on translation of basic environmental health science research to clinical and public health applications. This yearly competition is open to all universities submission of applications from universities which do not yet have a P30 grant from NIEHS is encouraged. In the past, NIEHS staff has worked with investigators from the University of Hawaii who were interested in environmental health concerns unique to the Pacific Islands. NIEHS funded a Center for Oceans and Human Health at the University of Hawaii combining the research of talented marine biologists and toxicologists. NIEHS also supports a community based participatory research program focusing on the respiratory health effects of exposure to volcanic emissions. NIEHS would welcome an application from the University of Hawaii and their collaborators for a Core Center grant and continues to be willing to discuss these possibilities with their lead researchers.

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Perchlorate - The Committee encourages the Institute to support clinical, mechanistic, and epidemiological studies that focus on establishing a better understanding of the long-term health effects of perchlorate exposure on humans and determining with greater certainty what perchlorate exposures are safe for the most vulnerable populations. The Committee encourages the NIEHS to give priority in the following areas: (1) clinical studies on humans or primates designed to provide information on the effects of long-term exposures to low doses of perchlorate; (2) the design and implementation of innovative epidemiological studies that assess the possible health effects of perchlorate exposure on the most vulnerable populations, including pregnant women and their fetuses and newborns, and involve appropriate control populations; and/or (3) in vitro studies of the perchlorate influence on placental and breast iodide transport using human tissues and animals studies, and the effects of perchlorate on development independent of effects on iodide transport. (p. 129-130)

Action taken or to be taken

NIEHS recognizes the importance of research to understand the long-term health effects of perchlorate on humans. We are working proactively with the extramural research community to encourage research applications on perchlorate toxicity in human and animal models. In this regard, we have communicated with all grantees studying the developmental basis of disease requesting that they consider studying developmental exposure to perchlorate and its potential links to disease and dysfunction later in life. We are planning to sponsor a symposium next year on Thyroid Function; Basic Biology, Toxicology and Translation to Human Risk, which will include a session on perchlorate toxicity to the human thyroid system. Finally, we will be publishing an article on perchlorate toxicity and our continuing interest in funding perchlorate research in the journal Environmental Health Perspectives. This journal reaches toxicology and environmental health researchers across the country and should stimulate additional grant applications in this important area.

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Risk Sciences - The Committee encourages NIEHS to establish a competitive, peer-reviewed extramural program to conduct research in risk sciences, including methodologies for assessment, management, analysis, and communication of risks from exposure to environmental chemicals. (p. 130)

Action taken or to be taken

Please refer to the item regarding Risk analysis on pages NIEHS-33 of this document for response to this Significant Item.